Conjugates comprising a selective carrier-linker-drug structure (e.g., an antibody-drug conjugate, or ADC), are attractive selective chemo-therapeutic molecules, as they combine ideal properties of selectivity to a target cell and cytotoxic drugs. Selective carriers include proteins, peptides and antibodies. By directing potent cytotoxic drugs to a target cell, the desired therapeutic effect may be enhanced in the target cell while minimizing the effect on non-targeted cells. Successful selective carrier-linker-drug conjugate development for a given target cell depends, among other factors, on optimization of carrier selection, linker stability in the bloodstream, sufficient linker immolation in the cell for release of an effective amount of the drug, cytotoxic drug potency and mode of linker-drug conjugation to the antibody. More particularly, effective carrier-drug conjugates are characterized by at least one or more of the following: (i) a carrier-drug conjugate formation method wherein the antibody retains sufficient specificity to a target and wherein the drug efficacy is maintained; (ii) carrier-drug conjugate stability sufficient to limit drug release in the blood; (iii) sufficient cell membrane transport efficiency (endocytosis) to achieve a therapeutic intracellular carrier-drug conjugate concentration; (iv) sufficient intracellular drug release from the carrier-drug conjugate sufficient to achieve a therapeutic drug concentration; and (v) drug cytotoxicity in nanomolar or sub-nanomolar amounts.
Problematically, effective blood stream stability and effective intracellular drug release from the carrier-drug conjugates are typically coupled and inversely related for selective carrier-drug conjugates known in the art such that conjugates that exhibit blood stability also exhibit poor intracellular drug release.
A need therefore exists for efficacious selective carrier-linker-drug conjugates that are stable in the bloodstream and that provide for effective intracellular drug release.